Type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the sarcoplasmic reticulum and plays a pivotal role in excitation-contraction coupling in heart. RyR2 is the major target for arrhythmogenic diseases, e.g., catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular cardiomyopathy (ARVC). To date, over 150 mutations have been identified in the RyR2 gene of CPVT and ARVC patients. It is widely believed that CPVT and ARVC mutations cause hyperactivation of Ca2+ release and result in ventricular arrhythmia by abnormal Ca2+ homeostasis in cardiac muscle. The RyR2 channel is known to be regulated by both cytoplasmic Ca2+ (Ca2+ induced Ca2+ release: CICR) and luminal Ca2+ (store overload induced Ca2+ release: SOICR). It is well documented that the SOICR threshold and termination levels are affected in the disease-associated mutations, whereas it remains unclear how these mutations affect CICR. CICR shows biphasic Ca2+ dependence against cytoplasmic Ca2+, thus the activity can be determined by three parameters: sensitivity to activating Ca2+, sensitivity to inactivating Ca2+, and the gain (i.e., peak activity). In this study, we expressed RyR2 channels carrying CPVT and ARVC mutations in HEK cells and tested their Ca2+ homeostasis by live-cell Ca2+ imaging using gene-encoded Ca2+ indicators for optical imaging (GECO) and calcium-measuring organelle-entrapped protein indicators (CEPIA). In addition, three parameters of CICR activity was determined with [3H]ryanodine binding assay. Our results suggest that the disease-associated mutations divergently affects the parameters of CICR depending on the sites for mutation. The underlying molecular mechanism will be discussed.